A rapid entry to amino acid derived diverse 3,4-dihydropyrazines and dihydro[1,2,3]triazolo[1,5-a]pyrazines through 1,3-dipolar cycloaddition

Article abstract of DOI:10.1039/c4ob00639a

An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium-copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00639a

Organic &
Biomolecular Chemistry
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A rapid entry to amino acid derived diverse 3,4-
dihydropyrazines and dihydro[1,2,3]triazolo[1,5-a]-
pyrazines through 1,3-dipolar cycloaddition†
Cite this: Org. Biomol. Chem., 2014,
12, 3976
Saurav Bera and Gautam Panda*
An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolo-
pyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from
amino acid derived common intermediates with high yields is described. Moreover, one-pot access to
optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium–copper co-
catalytic system has also been achieved in this work. The easy substrate availability and operational simpli-
city make the process suitable for further exploration.
Received 26th March 2014,
Accepted 14th April 2014
DOI: 10.1039/c4ob00639a
www.rsc.org/obc
Introduction
Click chemistry is a modular synthetic approach towards the
assembly of new molecular entities by efficiently and reliably
joining small units together. By applying this concept, it is
now possible to produce manmade compounds of enormous
diversity than what is currently known or available. The tra-
ditional cycloaddition between azides and acetylenes studied
by Huisgen1a–c in the 1960s led to the development of a
straightforward synthesis of 1,4- and 1,5-substituted 1,2,3-tri-
azoles as regioisomeric mixtures. This classical reaction gained
enormous importance after its discovery.1d The regio-selective
synthesis of 1,4-substituted 1,2,3-triazoles through the use of a
copper catalyst was established independently by Sharpless2a
and Meldal2b which ensured dramatic acceleration of the reac-
tion rate and lowering of the reaction temperature. The struc-
tural and electronic properties of 1,2,3-triazoles are applicable
in peptidomimetic chemistry for introducing global and local
conformational restrictions.3 1,2,3-Triazoles have been used
as replacements of backbone peptide bonds4 or to stabilize
turn5,6 or helical7 architectures by cyclization between side
chain or backbone modified amino acid residues.8 Several
compounds of the 1,2,3-triazole class possess a broad spec-
trum of biological properties including anti-HIV,9a anti-aller-
gic,9b anti-bacterial,9c and fungicidal activities.9d On the other
hand, piperazine fused triazole compounds are found in a
Fig. 1 Some important triazolo-piperazine derivatives.
number of biologically active natural products, synthetic
agents, and drugs.
Besides, 1,2,3-triazolo[1,5-a]quinoxaline 1 (Fig. 1) has also
shown good affinity toward benzodiazepine and adenosine
receptors.10a,b In view of the frequent occurrence of 1,2,3-tri-
azoles and piperazines in various biologically active com-
pounds, we envisioned that 4,5,6,7-tetrahydro[1,2,3]triazolo-
[1,5-a]pyrazines 2 and/or their fused analogues could be novel
pharmacophores or important building blocks. Only a few
methods are available in the literature for the synthesis of
compounds of type 2 11 and of its 6-keto derivatives.12 Most of
the syntheses used the conventional intramolecular cyclo-
addition between azides and terminal alkynes, limiting the
diversity of substitutions at C-3 and C-4 of the product.
Despite the significant interest in these heterocyclic systems in
medicinal chemistry,13 arising from its close structural simi-
larity to benzodiazepine drugs such as Estazolam 3 and Alpra-
zolam 4, synthetic methods for their preparation are
limited,14,15 and all chiral approaches to these compounds are
based on the construction of the molecules on carbohydrate
motifs.16
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
B.S. 10/1, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India.
E-mail: gautam.panda@gmail.com, gautam_panda@cdri.res.in;
Fax: +91-522-2771941; Tel: +91-522-2772450, 2772550
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00639a
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Scheme 3 Synthesis of 5-methyl-3,4-dihydropyrazine.
Scheme 1 Synthesis of amino acid derived substituted 5-methyl-3,4-
dihydropyrazine and dihydro[1,2,3]triazolo[1,5-a]pyrazines.
substrates in order to synthesize 1,2,3-triazole-fused bicyclic
compounds in high yields.
The derived azido compound 6a–e reacted smoothly with
allylbromide and NaH in the presence of dry DMF at 0 °C to
give 7a–e (Scheme 3). The peak at νmax 2108 cm−1 in the IR
spectra of the products clearly indicated the presence of the
azide functionality. Finally, 1,3-dipolar cycloaddition reaction
was carried out under reagent-free conditions by heating a
toluene solution of the azido alkene 7a–e at 100 °C for 2 h to
provide 5-methyl-3,4-dihydropyrazine in good yields. In the
13C NMR spectrum of 8a–e, the presence of carbon signals at
δ 162.8, 151.1, 155.2 and 20.7 suggested the presence of amide
carbonyl, olefinic quaternary as well as methine carbons.
Additionally, the methyl proton signal at δ 2.14 (d, J = 1.8 Hz,
allylic coupling) testified the location of a vinylic methyl
group. In addition, the Boc protection of 8 can be removed
using TFA in dry DCM to afford 9 which provides an additional
opportunity for diversity oriented synthesis through derivatiza-
tion of the resulting secondary amine.
With intermediate azido compounds 6a–f in hand, syn-
thesis of dihydro [1,2,3]triazolo[1,5-a]pyrazines was attempted.
Compounds 6a–f were treated with propargyl bromide and
NaH in the presence of dry DMF at 0 °C to furnish azido
alkynes 10a–f. As above, reagent-free conditions by heating a
toluene solution of the azidoalkene at 100 °C gave triazolo
[1,5-a]pyrazines 11a–f in good yields (Scheme 4). With these
optimized conditions, the scope of the reaction with terminal
alkynes was investigated. The copper catalyzed 1,3-dipolar
cycloaddition reaction proceeds well in both aqueous and
organic solvents under very simple experimental conditions.
In this case, the starting materials were fully consumed within
Our work centered on chemical synthesis and properties of
S-amino acid-derived chiral heterocycles and natural product-
like molecules.17 Recently, we have published a series of
amino acid derived benzoxazepines as antitumor agents in
breast cancer17b and a novel methodology for the synthesis of
trans-2,5-disubstituted morpholines, piperazines and thiomor-
pholines through a straightforward and modular pathway
involving iodine mediated 6-exo-trig cyclization.17e In conjunc-
tion with our continued interest, we hereby report an extremely
simple and mild method for the diversity oriented synthesis of
amino acid derived substituted dihydro[1,2,3]triazolo [1,5-a]-
pyrazines and their ring fused analogues (Scheme 1).
Results and discussion
The synthesis of the required substrates for 1,3-dipolar cyclo-
addition reaction began with S-amino acids 1a–f which were
converted to their methyl esters 2a–f followed by boc protec-
tion of primary amines to give 3a–f (Scheme 2). Ester reduction
to 4a–f proceeded smoothly, followed by tosyl protection of
primary alcohols affording 5a–f. Amino acid-derived azido sub-
strates 6a–f for intramolecular click reaction were synthesized
by an SN2 displacement of the corresponding tosylates with
NaN3. All of these steps were accomplished in excellent yields
and are amenable to easy scale-up. In this letter, we reveal
an effective integration of click chemistry into amino acid
Scheme 4 Synthesis of dihydro [1,2,3]triazolo[1,5-a]pyrazines under
Scheme 2 Synthesis of intermediates 6a–e.
palladium-copper catalysis.
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Scheme 6 Plausible reaction mechanism for the formation of
5-methyl-3,4-dihydropyrazine.
Scheme 5 Synthesis of tetrahydro[1,2,3]triazolo[1,5-a][1,4]diazocine.
30 min as monitored by TLC even at rt. This mild condition
instead of an unnecessary requirement of high temperatures
radically improves the utility of this reaction. In order to
increase the structural diversity, the functionality at the C-3
position of compound 11 was investigated. Thus, employment
of Pd(OAc)2/PPh3 as a catalyst and CuI as a cocatalyst along
with K2CO3 as a base allowed the reaction to proceed to com-
pletion within 1 h, affording exclusively the desired product
12a,c with a good yield (81%).
Scheme 7 Plausible reaction mechanism.
Another pathway was adopted for the synthesis of chiral
triazolo [1,5-a][1,4]diazocine from the common carbinol pre-
cursor (Scheme 5). Compound 4b was oxidized to aldehyde
13b which was subjected to HWE olefination in dry DCM (ratio
of E : Z = 95 : 5) without any further purification furnishing
14b. The double bond and the ester group were reduced simul-
taneously using LAH (3 equiv.) to produce 15b. Tosylation of
the primary alcohol 15b in the presence of p-toluenesulphonyl
chloride and triethyl amine followed by nucleophilic substi-
tution with sodium azide affords 17b. The azido compound
was treated with propargylbromide and NaH in the presence of
dry DMF at 0 °C to give 18b. Under similar 1,3-dipolar cyclo-
addition reaction conditions, 18b provided triazolo[1,5-a][1,4]-
diazocine 19b with an excellent yield.
The formation of 5-methyl-3,4-dihydropyrazine may be
rationalized by assuming that the 1,3-DAC reaction proceeds
through the generation of a triazoline intermediate 20, which
after nitrogen elimination leads to an aziridine intermediate
21 (Scheme 6). This quickly isomerizes to afford the imine–
enamine mixture.18 From the hitherto intermediate two possi-
bilities can arise, either the reaction can follow ‘path a’ giving
rise to 3,4-dihydropyrazine 24, or the reaction can follow ‘path
b’ yielding compound 23. Probably due to the greater stability
of compound 24 compared to 23 (the double resonance stabil-
ized with both the nitrogen atoms compared to the single
resonance stabilized with one nitrogen atom), compound 24 is
the sole product obtained.
A plausible reaction mechanism for the formation of com-
pound 12 could be explained by applying features of palladium
chemistry. The oxidative addition of aryl iodide 25 to Pd(0),
formed in situ through the interaction of palladium acetate
and triphenyl phosphine, affords the arylpalladium(II) complex
26 which undergoes transmetalation with copper-acetylide 27
to generate the arylalkynylpalladium complex 28 (Scheme 7).
This on reductive elimination of palladium(0) affords the ary-
lated internal alkyne 29. Palladium(0) then activates the triple
bond through a complex 30, in which palladium is stabilised
by the nitrogen in proximity. Insertion of palladium into the
triple bond possibly leads to the vinylidene like transition
state 31. The increase of electron density in the dipolarophile
due to the palladium insertion accelerates the cycloaddition
through a HOMO–LUMO interaction leading to the formation
of the desired cycloadduct 12 with regeneration of
palladium(0).
Conclusion
In summary, we have described a simple and powerful syn-
thetic route that provides access to chirally pure diverse
5-methyl-3,4-dihydropyrazine, triazolo[1,5-a]pyrazines and tri-
azolo[1,5-a][1,4]diazocine starting from commercially available
S-amino acid derived synthetic intermediates. The key step
involves 1,3-dipolar cycloaddition under reagent free con-
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ditions, giving heterocycles that can be further elaborated in 3H), 1.26 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ 154.9,
several ways, such as by nucleophilic substitution on the rings 144.9, 136.7, 132.5, 129.9, 129.1, 128.5, 127.9, 126.6, 79.7, 69.9,
as well as incorporation of substituents at the 6-position from 50.7, 37.1, 28.2, 21.5 ppm; MS (ESI): m/z 406 [M + H]+; Anal.
amino acid constituents.
Calcd for C21H27NO5S: C, 62.20; H, 6.71; N, 3.45; O, 19.73; S,
7.91. Found: C, 62.26; H, 6.74; N, 3.49.
(S)-2-(tert-Butoxycarbonylamino)propyl-4-methylbenzenesulfo-
nate 5c. Colourless oil; yield, 85%; Rf 0.51 (8/2, hexane–ethyl
acetate); [α]3D0 = −15.8 (c 0.25, CHCl3); IR (neat, cm−1): 3393,
Experimental section
General
1
2367, 1692, 1355, 1177, 932; H NMR (300 MHz, CDCl3) δ 7.64
IR spectra were recorded on a Perkin-Elmer FT-IR RXI spectro- (d, 2H, J = 8.1 Hz), 7.21 (d, 2H, J = 7.9 Hz), 4.98 (s, 1H),
meter. 1H NMR and 13C NMR spectra were recorded on a 3.84–3.71 (m, 3H), 2.28 (s, 3H), 1.26 (s, 9H), 0.99 (d, 3H, J = 6.5
Brucker DPX-200 (operating at 200 MHz for 1H and 50 MHz for Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 154.6, 144.6, 139.3,
1
13C) or DPX-300 (operating at 300 MHz for H and 75 MHz for 129.4, 128.4, 125.5, 78.8, 47.8, 27.7, 23.4, 16.4 ppm; MS (ESI):
13C) spectrometer using CDCl3 as the solvent. Tetramethyl- m/z 330 [M + H]+; Anal. Calcd for C15H23NO5S: C, 54.69;
1
silane (0.00 ppm) served as the internal standard in H NMR H, 7.04; N, 4.25; O, 24.28; S, 9.73. Found: C, 54.66; H, 7.14;
and CDCl3 (77.0 ppm) served as the internal standard in N, 4.29.
13C NMR. All spectra were recorded at 25 °C. Coupling con-
(S)-2-(tert-Butoxycarbonylamino)-4-methylpentyl-4-methylbenzene-
sulfonate 5d. Colourless oil; yield, 87%; Rf 0.50 (8/2, hexane–
stants (J values) are given in hertz (Hz). Chemical shifts are
expressed in parts per million (ppm). Mass spectra were
recorded by electron spray ionization (ESMS). Glycerol or
m-nitro benzyl alcohol was used as a matrix. Reactions were
monitored on silica gel TLC plates (coated with TLC grade
silica gel). Detecting agents used (for TLC) were iodine vapors
and/or spraying with an aqueous solution of vanillin in 10%
sulfuric acid followed by heating at 150 °C. Column chromato-
graphy was performed over silica gel (100–200 mesh) procured
from Qualigens (India) using freshly distilled solvents.
ethyl acetate); [α]3D0 = −11.34 (c 0.22, CHCl3); IR (neat, cm−1):
1
3500, 2962, 1737, 1364, 1178, 771; H NMR (300 MHz, CDCl3)
δ 7.68 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J = 7.7 Hz), 4.62 (s, 1H),
3.94–3.73 (m, 3H), 2.33 (s, 3H), 1.46 (d, 1H, J = 5.6 Hz), 1.30
(s, 9H), 1.17 (s, 2H), 0.77 (t, 6H, J = 5.4 Hz) ppm; 13C NMR
(75 MHz, CDCl3): δ 154.9, 144.6, 132.4, 129.6, 127.6, 79.1, 71.7,
47.4, 39.7, 28.0, 24.2, 22.5, 21.3 ppm; MS (ESI): m/z 372
[M + H]+; Anal. Calcd for C18H29NO5S: C, 58.20; H, 7.87;
N, 3.77; O, 21.53; S, 8.63. Found: C, 58.26; H, 7.84; N, 3.70.
(2S,3R)-2-(tert-Butoxycarbonylamino)-3-methylpentyl-4-methyl-
benzenesulfonate 5e. Colourless oil; yield, 86%; Rf 0.52 (8/2,
hexane–ethyl acetate); [α]3D0 = −21.13 (c 0.25, CHCl3); IR (neat,
Experimental procedures and characterization data
General experimental procedure for the synthesis of 5a–e.
Compounds 4a–e (1 equiv.) were dissolved in 20 mL dry DCM
and then it was cooled at 0 °C, followed by addition of Et3N
(2 equiv.) and p-toluene sulfonyl chloride (1.2 equiv.). Then it
was stirred for 3 h at RT and diluted with 30 mL water. The
aqueous layer was extracted with DCM (2 × 50 mL) and dried
over anhydrous sodium sulphate. The solvent was removed
under vacuum and the crude product was then chromato-
graphed over silica gel with the eluent AcOEt–hexane (1 : 9) to
afford the title compounds 5a–e.
1
cm−1): 3512, 2956, 1721, 1343, 1177, 769; H NMR (300 MHz,
CDCl3) δ 7.71 (d, 2H, J = 8.1 Hz), 7.27 (d, 2H, J = 7.9 Hz), 4.56
(d, 1H, J = 8.4 Hz), 3.98 (s, 2H), 3.49 (bs, 1H), 2.37 (s, 3H), 1.47
(s, 2H), 1.33 (s, 9H), 1.06–0.97 (m, 1H), 0.80–0.74 (m, 6H) ppm;
13C NMR (75 MHz, CDCl3): δ 155.2, 144.7, 132.4, 129.7, 127.7,
79.1, 68.0, 56.8, 38.6, 28.0, 23.8, 21.3, 15.0, 10.7 ppm; MS (ESI):
m/z 372 [M + H]+; Anal. Calcd for C15H23NO5S: C, 58.20; H,
7.87; N, 3.77; O, 21.53; S, 8.63. Found: C, 58.26; H, 7.82; N,
3.71.
General experimental procedure for the synthesis of
6a–f. To a stirred solution of compounds 5a–f (1 equiv.) in
anhydrous DMF (10 mL) sodium azide (2 equiv.) was added.
The reaction mixture was stirred for 2 h at 80 °C. The reaction
mixture was diluted with water (30 mL). The aqueous layer was
extracted with ethyl acetate (3 × 50 mL) and the organic layer
was dried over anhydrous Na2SO4. After concentration under
vacuum, the crude product was chromatographed on silica gel
(eluent = hexane–ethyl acetate, 9.2/0.8) to furnish compounds
6a–f (78% yield) as colourless oil.
(S)-2-(tert-Butoxycarbonylamino)-3-methylbutyl-4-methylbenzene-
sulfonate 5a. Colourless oil; yield, 86%; Rf 0.52 (8/2, hexane–
ethyl acetate); [α]3D0 = −11.69 (c 0.32, CHCl3); IR (neat, cm−1):
1
3504, 2960, 1729, 1369, 1175, 775; H NMR (300 MHz, CDCl3)
δ 7.70 (d, 2H, J = 8.2 Hz), 7.27 (d, 2H, J = 7.9 Hz), 4.55 (d, 1H,
J = 8.4 Hz), 3.99–3.95 (m, 2H), 3.43 (s, 1H), 2.37 (s, 3H),
1.76–1.67 (m, 1H), 1.33 (s, 9H), 0.80 (t, 6H, J = 8.1 Hz) ppm;
13C NMR (75 MHz, CDCl3): δ 155.4, 144.9, 132.5, 129.8, 127.8,
79.4, 70.0, 54.7, 28.8, 28.2, 21.5, 19.1 ppm; MS (ESI): m/z 358
[M + H]+; Anal. Calcd for C17H27NO5S: C, 57.12; H, 7.61;
N, 3.92; O, 22.38; S, 8.97. Found: C, 57.16; H, 7.64; N, 3.89.
(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropyl-4-methylbenzene-
sulfonate 5b. Colourless oil; yield, 88%; Rf 0.53 (8/2, hexane–
ethyl acetate); [α]D30 = −7.46 (c 0.26, CHCl3); IR (neat, cm−1):
(S)-tert-Butyl-1-azido-3-methylbutan-2-ylcarbamate 6a. Colour-
less oil; yield, 77%; Rf 0.60 (8/2, hexane–ethyl acetate); [α]D30
=
−31.15 (c 0.17, CHCl3); IR (neat, cm−1): 3348, 2971, 2101, 1701,
1507, 1169, 760; 1H NMR (300 MHz, CDCl3) δ 4.51 (s, 1H), 3.44
(s, 1H), 3.34 (d, 2H, J = 3.8 Hz), 1.74–1.67 (m, 1H), 1.38 (s, 9H),
0.86 (t, 6H, J = 6.4 Hz) ppm; 13C NMR (50 MHz, CDCl3) δ 155.4,
79.4, 55.5, 53.0, 29.7, 28.3, 19.4 ppm; MS (ESI): m/z 229
1
3508, 2959, 1716, 1360, 1177, 771; H NMR (300 MHz, CDCl3)
δ 7.66 (d, 2H, J = 8.0 Hz), 7.21 (d, 2H, J = 7.9 Hz), 7.10–6.96 (m,
5H), 4.75 (s, 1H), 4.03–3.80 (m, 3H), 2.73–2.66 (m, 2H), 2.32 (s,
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[M + H]+; Anal. Calcd for C10H20N4O2: C, 52.61; H, 8.83; N, was stirred for 1 h at RT. The reaction mixture was diluted with
24.54; O, 14.02. Found: C, 52.64; H, 8.85; N, 24.50.
water (30 mL). The aqueous layer was extracted with ethyl
acetate (2 × 50 mL) and the organic layer was dried over an-
hydrous Na2SO4. After concentration under vacuum, the crude
product was chromatographed on silica gel (eluent = hexane–
ethyl acetate, 9.4/0.6) to furnish the disubstituted morpholine
7a–e (80% yield).
(S)-tert-Butyl-1-azido-3-phenylpropan-2-ylcarbamate 6b. This
product was isolated as colourless oil. yield, 78%, Rf 0.61 (8/2,
hexane–ethyl acetate); [α]3D0 = −21.67 (c 0.18, CHCl3); IR (neat,
cm−1): 3455, 2975, 2110, 1716, 1513, 1162, 763; 1H NMR
(300 MHz, CDCl3) δ 7.25–7.10 (m, 5H), 4.63 (s, 1H), 3.88 (s,
1H), 3.37–3.15 (m, 2H), 2.77–2.66 (m, 2H), 1.34 (s, 9H) ppm;
(S)-tert-Butyl allyl(1-azido-3-methylbutan-2-yl)carbamate 7a.
13C NMR (75 MHz, CDCl3) δ 155.0, 137.0, 129.1, 128.5, 126.6, Colourless oil; yield, 80%; Rf 0.63 (8.5/1.5, hexane–ethyl
79.6, 53.1, 51.3, 38.1, 28.2 ppm; MS (ESI): m/z 277 [M + H]+; acetate); [α]D30 = −11.9 (c 0.12, CHCl3); IR (neat, cm−1): 3483,
1
Anal. Calcd for C14H20N4O2: C, 60.85; H, 7.30; N, 20.28; 2109, 1683, 1415, 1168, 766, 700; H NMR (300 MHz, CDCl3):
O, 11.58. Found: C, 60.80; H, 7.36; N, 20.23.
δ 5.87–5.78 (m, 1H), 5.12–5.04 (m, 2H), 3.81–3.52 (m, 3H), 3.33
(d, 2H, J = 9.2 Hz), 1.88–1.86 (m, 1H), 1.39 (s, 9H), 0.84 (dd,
6H, J1 = 6.5 Hz, J2 = 14.6 Hz) ppm; 13C NMR (75 MHz, CDCl3):
δ 155.5, 135.4, 116.1, 80.1, 67.7, 58.8, 45.8, 28.3, 28.2,
20.0 ppm; MS (ESI): m/z 269 [M + H]+; Anal. Calcd for
C13H24N4O2: C, 58.18; H, 9.01; N, 20.88; O, 11.92. Found: C,
58.20; H, 9.05; N, 20.80.
(S)-tert-Butyl-1-azidopropan-2-ylcarbamate 6c. Colourless oil;
yield, 78%; Rf 0.63 (8/2, hexane–ethyl acetate); [α]3D0 = −24.34
(c 0.16, CHCl3); IR (neat, cm−1): 3352, 2965, 2107, 1689, 1512,
1160, 765; 1H NMR (300 MHz, CDCl3) δ 4.61 (s, 1H), 3.77 (s,
1H), 3.30–3.22 (m, 2H), 1.37 (s, 9H), 1.11 (d, 3H, J = 6.7 Hz)
ppm; 13C NMR (75 MHz, CDCl3) δ 154.9, 79.4, 55.8, 46.1, 28.2,
18.0 ppm; MS (ESI): m/z 201 [M + H]+; Anal. Calcd for
(S)-tert-Butyl allyl(1-azido-3-phenylpropan-2-yl)carbamate 7b.
C8H16N4O2: C, 47.99; H, 8.05; N, 27.98; O, 15.98. Found: C, Colourless oil; yield, 81%; Rf 0.62 (8.5/1.5, hexane–ethyl
48.04; H, 8.01; N, 27.91.
acetate); [α]3D0 = −8.61 (c 0.15, CHCl3); IR (neat, cm−1): 2977,
2108, 1690, 1411, 1165, 1024, 758; H NMR (300 MHz, CDCl3):
1
(S)-tert-Butyl-1-azido-4-methylpentan-2-ylcarbamate 6d. Colour-
less oil; yield, 78%; Rf 0.60 (8/2, hexane–ethyl acetate);
[α]3D0 = −22.19 (c 0.15, CHCl3); IR (neat, cm−1): 3359, 2977,
δ 7.18–7.07 (m, 5H), 5.59–5.47 (m, 1H), 4.95 (d, 2H, J =
13.5 Hz), 3.87–3.45 (m, 4H), 3.17 (d, 1H, J = 9.5 Hz), 2.96–2.63
(m, 2H), 1.35 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ 154.4,
136.6, 128.8, 128.6, 128.1, 126.1, 115.9, 79.6, 54.0, 53.5, 45.9,
37.8, 27.7 ppm; MS (ESI): m/z 317 [M + H]+; Anal. Calcd for
C17H24N4O2: C, 64.53; H, 7.65; N, 17.71; O, 10.11. Found:
C, 64.50; H, 7.69; N, 17.78.
(S)-tert-Butyl allyl(1-azidopropan-2-yl)carbamate 7c. Colour-
less oil; yield, 80%; Rf 0.61 (8.5/1.5, hexane–ethyl acetate);
[α]3D0 = −14.39 (c 0.17, CHCl3); IR (neat, cm−1): 3486, 2112,
1689, 1410, 1167, 765, 700; 1H NMR (300 MHz, CDCl3):
δ 5.76–5.74 (m, 1H), 5.09–5.02 (m, 2H), 4.02–3.68 (m, 3H), 3.44
(s, 1H), 3.12 (q, 1H, J = 5.8 Hz), 1.39 (s, 9H), 1.13 (d, 3H, J =
6.9 Hz) ppm; MS (ESI): m/z 241 [M + H]+; Anal. Calcd for
C11H20N4O2: C, 54.98; H, 8.39; N, 23.32; O, 13.32. Found: C,
54.93; H, 8.43; N, 23.38.
1
2112, 1700, 1523, 1162, 757; H NMR (300 MHz, CDCl3) δ 4.54
(s, 1H), 3.73 (s, 1H), 3.34–3.22 (m, 2H), 1.65–1.53 (m, 1H), 1.37
(s, 9H), 1.31–1.18 (m, 2H), 0.85 (d, 6H, J = 4.8 Hz) ppm;
13C NMR (75 MHz, CDCl3) δ 155.2, 79.4, 55.1, 48.5, 45.1, 28.3,
24.7, 22.9, 22.0 ppm; MS (ESI): m/z 243 [M + H]+; Anal. Calcd
for C11H22N4O2: C, 54.52; H, 9.15; N, 23.12; O, 13.21. Found: C,
54.48; H, 9.19; N, 23.20.
tert-Butyl (2S,3R)-1-azido-3-methylpentan-2-ylcarbamate 6e.
Colourless oil; yield, 78%; Rf 0.61 (8/2, hexane–ethyl acetate);
[α]3D0 = −24.6 (c 0.16, CHCl3); IR (neat, cm−1): 3378, 2963, 2114,
1709, 1521, 1162, 769; 1H NMR (300 MHz, CDCl3) δ 4.58 (d,
1H, J = 8.0 Hz), 3.51 (s, 1H), 3.35 (s, 2H), 1.48–1.44 (m, 2H),
1.38 (s, 9H), 1.17–0.98 (m, 1H), 0.83 (t, 6H, J = 6.7 Hz) ppm;
13C NMR (75 MHz, CDCl3) δ 155.4, 79.3, 54.3, 52.7, 36.2, 28.2,
25.0, 15.3, 11.1 ppm; MS (ESI): m/z 243 [M + H]+; Anal. Calcd
(S)-tert-Butyl allyl(1-azido-4-methylpentan-2-yl)carbamate 7d.
for C11H22N4O2: C, 54.52; H, 9.15; N, 23.12; O, 13.21. Found: C, Colourless oil; yield, 81%; Rf 0.60 (8.5/1.5, hexane–ethyl
54.57; H, 9.20; N, 23.08.
acetate); [α]3D0 = −9.72 (c 0.15, CHCl3); IR (neat, cm−1): 3488,
2962, 2110, 1683, 1413, 1168, 762; H NMR (300 MHz, CDCl3):
1
(S)-tert-Butyl-1-azido-4-(methylthio)butan-2-ylcarbamate 6f.
This product was isolated as colourless oil. Yield, 76%, Rf 0.62
(8/2, hexane–ethyl acetate); [α]3D0 = −39.72 (c 0.15, CHCl3); IR
(neat, cm−1): 3478, 2977, 2119, 1752, 1518, 1166, 842, 760;
1H NMR (300 MHz, CDCl3) δ 3.77 (d, 1H, J = 2.9 Hz), 3.36–3.31
(m, 2H), 2.60–2.43 (m, 3H), 2.03 (s, 3H), 1.75–1.64 (m, 1H),
1.38 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 154.4, 80.9,
57.6, 52.1, 36.1, 32.3, 28.3, 15.4 ppm; MS (ESI): m/z 261
[M + H]+; Anal. Calcd for C10H20N4O2S: C, 46.13; H, 7.74;
N, 21.52; O, 12.29; S, 12.32. Found: C, 46.16; H, 7.78; N, 21.54.
General experimental procedure for the synthesis of
7a–e. To a stirred solution of compounds 6a–e (1 equiv.) in
anhydrous DMF (10 mL) NaH (19 mg, 60% suspension in
mineral oil) was added at 0 °C. Then the required amount of
allylbromide (1 equiv.) was added at 0 °C. The reaction mixture
δ 5.78 (s, 1H), 5.10–5.01 (m, 2H), 4.04–3.97 (m, 1H), 3.66 (d,
2H, J = 13.6 Hz), 3.49–3.26 (m, 1H), 3.13–3.07 (m, 1H), 1.48 (d,
2H, J = 9.9 Hz), 1.39 (s, 10H), 0.89 (t, 6H, J = 5.9 Hz) ppm;
13C NMR (75 MHz, CDCl3): δ 155.2, 135.5, 115.9, 80.0, 53.5,
53.2, 50.3, 39.0, 28.2, 24.7, 24.4, 22.0 ppm; MS (ESI): m/z 283
[M + H]+; Anal. Calcd for C14H26N4O2: C, 59.55; H, 9.28; N,
19.84; O, 11.33. Found: C, 59.50; H, 9.22; N, 19.79.
tert-Butyl allyl((2S,3R)-1-azido-3-methylpentan-2-yl)carbamate
7e. Colourless oil; yield, 80%; Rf 0.62 (8.5/1.5, hexane–ethyl
acetate); [α]3D0 = −7.6 (c 0.15, CHCl3); IR (neat, cm−1): 3388,
1
2117, 1680, 1423, 1208, 762, 677; H NMR (300 MHz, CDCl3):
δ 5.83–5.81 (m, 1H), 5.09–5.02 (m, 2H), 3.73 (bs, 1H), 3.65–3.48
(m, 3H), 3.36 (s, 1H), 1.39 (s, 9H), 1.07–0.94 (m, 3H), 0.83–0.78
(m, 6H) ppm; 13C NMR (75 MHz, CDCl3): δ 154.8, 135.5, 116.0,
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80.1, 67.6, 57.5, 56.1, 38.5, 28.3, 24.5, 15.9, 11.6 ppm; MS
(ESI): m/z 283 [M + H]+; Anal. Calcd for C14H26N4O2: C,
59.55; H, 9.28; N, 19.84; O, 11.33. Found: C, 59.60; H, 9.23; N,
19.80.
General experimental procedure for the synthesis of 8a–e.
Compounds 7a–e (1 equiv.) were dissolved in 20 mL dry
toluene, and then it was heated up to 100 °C and stirred for
2 h. The reaction mixture was diluted with water (30 mL). The
aqueous layer was extracted with ethyl acetate (3 × 50 mL) and
the organic layer was dried over anhydrous Na2SO4. After con-
centration under vacuum, the crude product was chromato-
graphed on silica gel (eluent = hexane–ethyl acetate, 8/2) to
furnish 8a–e (80% yield) as colourless oil.
(S)-tert-Butyl 2-sec-butyl-5-methyl-3,4-dihydropyrazine-1(2H)-
carboxylate 8e. Colourless oil; yield, 85%; Rf 0.42 (7/3, hexane–
ethyl acetate); [α]D30 = +34.7 (c 0.15, CHCl3); IR (neat, cm−1):
3471, 2356, 1703, 1370, 1155, 768, 672; 1H NMR (300 MHz,
CDCl3): δ 4.67 (s, 1H), 4.16–4.12 (m, 1H), 4.04–3.98 (m, 1H),
3.63–3.57 (m, 1H), 2.16 (s, 3H), 1.62–1.53 (s, 1H), 1.48 (s, 9H),
1.39–1.27 (m, 2H), 1.14–1.02 (m, 1H), 0.85–0.77 (m, 6H) ppm;
13C NMR (75 MHz, CDCl3): δ 163.3, 155.8, 151.8, 83.8, 56.8,
48.6, 37.2, 27.9, 25.6, 20.8, 16.4, 11.6 ppm; MS (ESI): m/z 255
[M + H]+; Anal. Calcd for C14H26N2O2: C, 66.10; H, 10.30; N,
11.01; O, 12.58. Found: C, 66.17; H, 10.36; N, 11.06.
General experimental procedure for the synthesis of 9. To a
stirred solution of compounds 8 (1 equiv.) in anhydrous DCM
(S)-tert-Butyl 2-isopropyl-5-methyl-3,4-dihydropyrazine-1(2H)- (10 mL) TFA (1 equiv.) was added at 0 °C. The resulting solu-
carboxylate 8a. Colourless oil; yield, 85%; Rf 0.45 (7/3, hexane–
ethyl acetate); [α]D30 = +35.6 (c 0.22, CHCl3); IR (neat, cm−1):
2976, 1763, 1681, 1270, 1161, 1221, 778; 1H NMR (300 MHz,
CDCl3): δ 4.20 (s, 1H), 4.08–3.99 (m, 2H), 3.63–3.56 (m, 1H),
2.16 (s, 3H), 1.89–1.77 (m, 1H), 1.48 (s, 9H), 1.39–1.26 (m, 1H),
0.85 (dd, 6H, J1 = 3.1 Hz, J2 = 6.7 Hz) ppm; 13C NMR (75 MHz,
CDCl3): δ 163.3, 155.6, 151.9, 83.8, 58.1, 49.0, 30.4, 27.9, 20.8,
tion was then warmed to RT and it was stirred for 30 min. The
aqueous layer was extracted with DCM (3 × 50 mL) and the
organic layer was dried over anhydrous Na2SO4. After concen-
tration under vacuum, the crude product was chromato-
graphed on silica gel (eluent = hexane–ethyl acetate, 7.5/2.5) to
furnish compound 9.
(S)-2-Isopropyl-5-methyl-1,2,3,4-tetrahydropyrazine 9a. Colour-
20.0, 19.4 ppm; MS (ESI): m/z 241 [M + H]+; Anal. Calcd for less oil; yield, 74%; Rf 0.41 (6/4, hexane–ethyl acetate); [α]D30
=
C13H24N2O2: C, 64.97; H, 10.07; N, 11.66; O, 13.31. Found: +23.12 (c 0.14, CHCl3); IR (neat, cm−1): 3721, 2352, 1659, 1237,
C, 64.91; H, 10.12; N, 11.60.
1011, 779, 674; 1H NMR (300 MHz, CDCl3): δ 4.37 (s, 1H),
3.70–3.62 (m, 3H), 2.78 (bs, 1H), 2.11 (s, 3H), 1.79–1.72
(m, 1H), 0.93–0.89 (m, 6H) ppm; 13C NMR (75 MHz, CDCl3):
δ 126.6, 109.3, 70.6, 48.6, 32.3, 19.8 ppm; MS (ESI): m/z 141
[M + H]+; Anal. Calcd for C8H16N2: C, 68.52; H, 11.50; N, 19.98.
Found: C, 68.57; H, 11.47; N, 19.96.
(S)-tert-Butyl 2-benzyl-5-methyl-3,4-dihydropyrazine-1(2H)-
carboxylate 8b. Colourless oil; yield, 85%; Rf 0.43 (7/3, hexane–
ethyl acetate); [α]3D0 = +31.24 (c 0.20, CHCl3); IR (neat, cm−1):
3366, 2338, 1717, 1283, 1154, 1024, 762; 1H NMR (300 MHz,
CDCl3): δ 7.20–7.06 (m, 5H), 5.60 (s, 1H), 4.39–4.33 (m, 1H),
3.81–3.75 (m, 1H), 3.50–3.43 (m, 1H), 2.88–2.82 (m, 1H),
2.70–2.62 (m, 1H), 2.14 (d, 3H, J = 1.0 Hz), 1.45 (s, 9H) ppm;
13C NMR (75 MHz, CDCl3): δ 162.9, 154.8, 150.8, 136.6, 128.9,
128.2, 126.4, 83.5, 54.1, 48.8, 37.4, 27.5, 20.5 ppm; MS (ESI):
m/z 289 [M + H]+; Anal. Calcd for C17H24N2O2: C, 70.80; H,
8.39; N, 9.71; O, 11.10. Found: C, 70.86; H, 8.32; N, 9.68.
(S)-2-Isobutyl-5-methyl-1,2,3,4-tetrahydropyrazine 9d. Colour-
less oil; yield, 73%; Rf 0.42 (6/4, hexane–ethyl acetate); [α]D30
=
+13.46 (c 0.15, CHCl3); IR (neat, cm−1): 3709, 2351, 1670, 1222,
1031, 776, 678; 1H NMR (300 MHz, CDCl3): δ 4.58 (s, 1H),
3.56–3.48 (m, 1H), 3.30–3.19 (m, 2H), 2.76–2.65 (m, 1H), 2.13
(s, 3H), 1.69–1.61 (m, 1H), 1.30–1.20 (m, 2H), 0.88–0.85 (m,
(S)-tert-Butyl 2,5-dimethyl-3,4-dihydropyrazine-1(2H)-carboxy- 6H) ppm; 13C NMR (75 MHz, CDCl3): δ 126.0, 108.0, 59.9, 49.8,
40.3, 25.0, 23.3, 19.5 ppm; MS (ESI): m/z 155 [M + H]+; Anal.
late 8c. Colourless oil; yield, 85%; Rf 0.44 (7/3, hexane–ethyl
acetate); [α]3D0 = +27.69 (c 0.19, CHCl3); IR (neat, cm−1): 2948,
Calcd for C9H18N2: C, 70.08; H, 11.76; N, 18.16. Found: C,
70.04; H, 11.78; N, 18.12.
1
1760, 1642, 1279, 1153, 1201, 770; H NMR (300 MHz, CDCl3):
δ 4.95 (s, 1H), 4.40–4.32 (m, 1H), 3.75–3.74 (m, 2H), 2.19 (d,
(S)-2-sec-Butyl-5-methyl-1,2,3,4-tetrahydropyrazine 9e. Colour-
3H, J = 1.8 Hz), 1.48 (s, 10H), 1.18 (d, 3H, J = 1.6 Hz) ppm; 13C less oil; yield, 75%; Rf 0.40 (6/4, hexane–ethyl acetate); [α]D30
=
NMR (75 MHz, CDCl3): δ 162.8, 155.2, 151.1, 83.6, 52.7, 48.9, +19.6 (c 0.15, CHCl3); IR (neat, cm−1): 3712, 2360, 1638, 1218,
27.7, 20.7, 17.7 ppm; MS (ESI): m/z 213 [M + H]+; Anal. Calcd 1026, 771, 672; 1H NMR (300 MHz, CDCl3): δ 4.57 (s, 1H),
for C11H20N2O2: C, 62.23; H, 9.50; N, 13.20; O, 15.07. Found: C, 3.79–3.69 (m, 1H), 3.38 (d, 2H, J = 5.3 Hz), 2.40 (bs, 1H), 2.14
62.26; H, 9.56; N, 13.26.
(S)-tert-Butyl
(s, 3H), 1.49–1.36 (m, 3H), 1.18–1.07 (m, 1H), 0.88–0.84 (m,
6H) ppm; 13C NMR (75 MHz, CDCl3): δ 125.8, 108.0, 66.4, 48.6,
2-isobutyl-5-methyl-3,4-dihydropyrazine-1(2H)-
carboxylate 8d. Colourless oil; yield, 85%; Rf 0.45 (7/3, hexane– 41.3, 24.8, 19.8, 18.0, 12.0 ppm; MS (ESI): m/z 155 [M + H]+;
ethyl acetate); [α]3D0 = +37.19 (c 0.18, CHCl3); IR (neat, cm−1): Anal. Calcd for C9H18N2: C, 70.08; H, 11.76; N, 18.16. Found:
1
3440, 1718, 1651, 1286, 1157, 768; H NMR (300 MHz, CDCl3): C, 70.01; H, 11.79; N, 18.10.
δ 4.70 (s, 1H), 4.33–4.27 (m, 1H), 3.94–3.88 (m, 1H), 3.65–3.57
General experimental procedure for the synthesis of
(m, 1H), 2.18 (d, 3H, J = 2.3 Hz), 1.48 (s, 10H), 1.41 (d, 1H, J = 10a–f. To a stirred solution of compounds 6a–e (1 equiv.) in
5.3 Hz), 1.35–1.24 (m, 2H), 0.87–0.84 (m, 6H) ppm; 13C NMR anhydrous DMF (10 mL), NaH (18 mg, 60% suspension in
(75 MHz, CDCl3): δ 163.1, 155.3, 150.9, 83.6, 51.1, 49.7, 40.1, mineral oil) was added at 0 °C. Then the required amount of
27.6, 24.8, 23.0, 21.2, 20.6 ppm; MS (ESI): m/z 255 [M + H]+; propargyl bromide (1 equiv.) was added at 0 °C. The reaction
Anal. Calcd for C14H26N2O2: C, 66.10; H, 10.30; N, 11.01; O, mixture was stirred for 1 h at RT. The reaction mixture was
12.58. Found: C, 66.16; H, 10.25; N, 11.07.
diluted with water (30 mL). The aqueous layer was extracted
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with ethyl acetate (2 × 50 mL) and the organic layer was dried C14H24N4O2: C, 59.98; H, 8.63; N, 19.98; O, 11.41. Found: C,
over anhydrous Na2SO4. After concentration under vacuum, 59.92; H, 8.69; N, 19.92.
(S)-tert-Butyl 1-azido-4-(methylthio)butan-2-yl(prop-2-ynyl)-
carbamate 10f. Colourless oil; yield, 81%; Rf 0.63 (8.5/1.5,
hexane–ethyl acetate); [α]3D0 = −30.1 (c 0.15, CHCl3); IR (neat,
the crude product was chromatographed on silica gel (eluent =
hexane–ethyl acetate, 9.6/0.4) to furnish 10a–f (78–81% yield).
(S)-tert-Butyl 1-azido-3-methylbutan-2-yl(prop-2-ynyl)carbamate
10a. Colourless oil; yield, 78%; Rf 0.65 (8.5/1.5, hexane–ethyl cm−1): 3411, 2167, 2115, 1420, 1131, 869, 775, 720; 1H NMR
acetate); [α]3D0 = −41.7 (c 0.12, CHCl3); IR (neat, cm−1): 3421, (300 MHz, CDCl3): δ 3.78–3.77 (m, 2H), 3.36–3.31 (m, 2H), 2.60
1
2123, 2102, 1641, 1166, 793, 741; H NMR (300 MHz, CDCl3): (s, 1H), 2.49–2.43 (m, 2H), 2.03 (s, 3H), 1.75–1.64 (m, 3H), 1.38
δ 4.69 (d, 1H, J = 13.0 Hz), 4.15 (dd, 2H, J1 = 4.2 Hz, J2 = 13.4 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ 155.8, 81.2, 80.0,
Hz), 4.09 (s, 1H), 3.33 (d, 1H, J = 4.1 Hz), 2.74 (d, 1H, J = 2.3 72.2, 56.8, 48.6, 37.2, 30.5, 28.2, 16.4 ppm; MS (ESI): m/z 299
Hz), 2.18–2.12 (m, 1H), 1.42 (s, 9H), 0.86 (t, 6H, J = 7.0 Hz) [M + H]+; Anal. Calcd for C13H22N4O2S: C, 52.32; H, 7.43; N,
ppm; 13C NMR (75 MHz, CDCl3): δ 155.2, 80.8, 78.8, 54.1, 52.4, 18.78; O, 10.72; S, 10.75. Found: C, 52.37; H, 7.40; N, 18.81.
46.4, 35.9, 27.9, 24.7, 15.0 ppm; MS (ESI): m/z 267 [M + H]+;
Anal. Calcd for C13H22N4O2: C, 58.62; H, 8.33; N, 21.04; O, 11a–e. The procedure was followed as described for 8a–e.
General experimental procedure for the synthesis of
(S)-tert-Butyl 6-isopropyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyra-
zine-5(4H)-carboxylate 11a. Colourless oil; yield, 80%; Rf 0.40
12.01. Found: C, 58.68; H, 8.29; N, 21.10.
(S)-tert-Butyl 1-azido-3-phenylpropan-2-yl(prop-2-ynyl)carba-
mate 10b. Colourless oil; yield, 79%; Rf 0.64 (8.5/1.5, hexane– (7/3, hexane–ethyl acetate); [α]3D0 = +11.12 (c 0.15, CHCl3); IR
ethyl acetate); [α]3D0 = −38.9 (c 0.12, CHCl3); IR (neat, cm−1): (neat, cm−1): 3312, 1721, 1212, 1067, 783, 656; 1H NMR
3334, 2137, 2111, 1661, 1472, 1166, 762, 702; 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 5.06 (bs, 1H), 4.69 (d, 1H, J =
(300 MHz, CDCl3): δ 7.21–7.10 (m, 5H), 4.00–3.59 (m, 3H), 3.26 12.8 Hz), 4.18–4.12 (m, 3H), 1.53–1.49 (m, 1H), 1.43 (s, 9H),
(d, 1H, J = 10.3 Hz), 2.95–2.82 (m, 2H), 1.37 (s, 9H), 1.32 (d, 0.91 (d, 3H, J = 6.5 Hz), 0.85 (d, 3H, J = 6.6 Hz) ppm; 13C NMR
2H, J = 4.5 Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 153.8, 137.7, (75 MHz, CDCl3) δ 155.5, 154.2, 129.1, 81.1, 54.7, 46.7, 36.7,
129.0, 128.9, 128.5, 81.2, 80.0, 72.2, 58.8, 52.0, 31.8, 30.5, 28.2, 26.9, 19.8 ppm; MS (ESI): m/z 267 [M + H]+; Anal. Calcd
28.2 ppm; MS (ESI): m/z 315 [M + H]+; Anal. Calcd for for C13H22N4O2: C, 58.62; H, 8.33; N, 21.04; O, 12.01. Found: C,
C17H22N4O2: C, 64.95; H, 7.05; N, 17.82; O, 10.18. Found: C, 58.67; H, 8.31; N, 21.10.
(S)-tert-Butyl
6-benzyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyra-
64.90; H, 7.00; N, 17.88.
zine-5(4H)-carboxylate 11b. Colourless oil; yield, 81%; Rf 0.41
(7/3, hexane–ethyl acetate); [α]3D0 = +15.4 (c 0.13, CHCl3); IR
(neat, cm−1): 3245, 3013, 1694, 1398, 1165, 759; 1H NMR
(300 MHz, CDCl3) δ 7.57 (s, 1H), 7.28–7.17 (m, 3H), 7.08 (d,
2H, J = 7.1 Hz), 5.05–5.00 (m, 2H), 4.53 (d, 1H, J = 13.2 Hz),
4.43–4.37 (m, 1H), 4.19 (d, 1H, J = 10.4 Hz), 2.73–2.66 (m, 1H),
2.57–2.50 (m, 1H), 1.36 (s, 9H) ppm; 13C NMR (75 MHz,
CDCl3) δ 153.7, 136.3, 129.2, 129.0, 128.6, 126.9, 81.2, 61.1,
58.0, 47.8, 36.4, 28.1 ppm; MS (ESI): m/z 315 [M + H]+; Anal.
Calcd for C17H22N4O2: C, 64.95; H, 7.05; N, 17.82; O, 10.18.
(S)-tert-Butyl 1-azidopropan-2-yl(prop-2-ynyl)carbamate 10c.
Colourless oil; yield, 80%; Rf 0.62 (8.5/1.5, hexane–ethyl
acetate); [α]3D0 = −47.6 (c 0.15, CHCl3); IR (neat, cm−1): 3473,
1
2137, 2107, 1446, 1153, 761, 704; H NMR (300 MHz, CDCl3):
δ 4.40–4.23 (m, 1H), 4.02–3.88 (m, 3H), 3.48 (t, 1H, J = 11.2 Hz),
3.24–3.18 (m, 1H), 1.42 (s, 9H), 1.21 (d, 3H, J = 6.7 Hz) ppm;
13C NMR (75 MHz, CDCl3): δ 153.8, 81.1, 80.5, 70.6, 50.1, 44.8,
35.9, 28.2, 15.9 ppm; MS (ESI): m/z 239 [M + H]+; Anal. Calcd
for C11H18N4O2: C, 55.44; H, 7.61; N, 23.51; O, 13.43. Found: C,
55.40; H, 7.65; N, 23.46.
(S)-tert-Butyl
1-azido-4-methylpentan-2-yl(prop-2-ynyl)carba- Found: C, 64.90; H, 7.10; N, 17.88.
mate 10d. Colourless oil; yield, 81%; Rf 0.66 (8.5/1.5, hexane–
ethyl acetate); [α]D30 = −42.4 (c 0.14, CHCl3); IR (neat, cm−1):
3431, 2132, 2104, 1441, 1161, 782, 704; 1H NMR (300 MHz,
CDCl3): δ 4.58 (d, 1H, J = 7.8 Hz), 3.72 (s, 1H), 3.33–3.32 (m,
2H), 1.58–1.56 (m, 1H), 1.42 (s, 2H), 1.37 (s, 9H), 1.29–1.19 (m,
2H), 0.85 (d, 6H, J = 6.5 Hz) ppm; 13C NMR (75 MHz, CDCl3):
δ 153.9, 81.3, 78.1, 72.2, 53.3, 49.3, 38.7, 30.5, 28.2, 24.8, 24.5,
21.6 ppm; MS (ESI): m/z 281 [M + H]+; Anal. Calcd for
C14H24N4O2: C, 59.98; H, 8.63; N, 19.98; O, 11.41. Found: C,
59.90; H, 8.67; N, 19.90.
tert-Butyl (2S,3R)-1-azido-3-methylpentan-2-yl(prop-2-ynyl)-
carbamate 10e. Colourless oil; yield, 79%; Rf 0.64 (8.5/1.5,
hexane–ethyl acetate); [α]3D0 = −37.6 (c 0.18, CHCl3); IR (neat,
cm−1): 3489, 2122, 2105, 1419, 1134, 781, 723; 1H NMR
(300 MHz, CDCl3): δ 4.72–4.62 (m, 1H), 3.92–3.75 (m, 1H),
3.43–3.34 (m, 3H), 1.41 (s, 9H), 1.37 (s, 3H), 1.07–1.02 (s, 1H),
0.84 (d, 6H, J = 6.3 Hz) ppm; 13C NMR (75 MHz, CDCl3):
δ 154.8, 81.2, 80.0, 72.2, 57.5, 56.1, 38.5, 34.1, 28.3, 24.5, 15.9,
11.6 ppm; MS (ESI): m/z 281 [M + H]+; Anal. Calcd for
(S)-tert-Butyl
6-methyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyra-
zine-5(4H)-carboxylate 11c. Colourless oil; yield, 83%; Rf 0.42
(7/3, hexane–ethyl acetate); [α]3D0 = +11.7 (c 0.11, CHCl3); IR
(neat, cm−1): 3454, 1761, 1243, 1025, 791, 679; 1H NMR
(300 MHz, CDCl3) δ 7.41 (s, 1H), 4.95–4.90 (s, 1H), 4.78 (bs,
1H), 4.32 (d, 1H, J = 12.9 Hz), 4.23–4.18 (m, 2H), 1.35 (s, 9H),
1.01 (d, 3H, J = 6.9 Hz) ppm; 13C NMR (75 MHz, CDCl3)
δ 155.5, 153.4, 128.8, 80.7, 49.9, 44.5, 35.8, 27.8, 15.5 ppm; MS
(ESI): m/z 239 [M + H]+; Anal. Calcd for C11H18N4O2: C, 55.44;
H, 7.61; N, 23.51; O, 13.43. Found: C, 55.40; H, 7.67; N, 23.58.
(S)-tert-Butyl 6-isobutyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyra-
zine-5(4H)-carboxylate 11d. Colourless oil; yield, 80%; Rf 0.43
(7/3, hexane–ethyl acetate); [α]3D0 = +16.4 (c 0.15, CHCl3); IR
(neat, cm−1): 3468, 2921, 2257, 1781, 1491, 1221, 761; H NMR
1
(300 MHz, CDCl3) δ 7.44 (s, 1H), 5.08 (d, 1H, J = 14.2 Hz), 4.74
(bs, 1H), 4.37 (d, 1H, J = 12.9 Hz), 4.25 (d, 1H, J = 4.4 Hz), 4.20
(d, 1H, J = 4.6 Hz), 4.12 (d, 1H, J = 15.7 Hz), 1.41 (s, 9H), 0.86
(q, 6H, J = 6.4 Hz), 0.77 (d, 3H, J = 6.6 Hz) ppm; 13C NMR
(75 MHz, CDCl3) δ 154.2, 153.5, 128.7, 80.7, 49.0, 38.3, 29.3,
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27.8, 24.4, 22.5, 21.7 ppm; MS (ESI): m/z 281 [M + H]+; Anal. Rf 0.52 (8/2, hexane–ethyl acetate); [α]D30 = +26.9 (c 0.13, CHCl3);
Calcd for C14H24N4O2: C, 59.98; H, 8.63; N, 19.98; O, 11.41. IR (neat, cm−1): 3437, 1776, 1434, 1265, 1082, 763, 671; 1H
Found: C, 59.92; H, 8.61; N, 19.95.
(S)-tert-Butyl 6-sec-butyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyra-
NMR (300 MHz, CDCl3) δ 7.33–7.23 (m, 5H), 4.40–4.10 (m, 3H),
3.59–3.50 (m, 1H), 3.25–3.21 (m, 1H), 1.44 (s, 9H), 1.27 (d, 3H,
zine-5(4H)-carboxylate 11e. Colourless oil; yield, 81%; Rf 0.41 J = 4.7 Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 154.6, 131.6,
(7/3, hexane–ethyl acetate); [α]3D0 = +17.6 (c 0.14, CHCl3); IR 128.9, 128.2, 127.8, 126.0, 122.9, 81.7, 60.0, 56.0, 34.6, 28.5,
(neat, cm−1): 3435, 2961, 2341, 1768, 1420, 1209, 763; H NMR 14.0 ppm; MS (ESI): m/z 315 [M + H]+; Anal. Calcd for
1
(300 MHz, CDCl3) δ 7.45 (s, 1H), 5.07 (bs, 1H), 4.70 (d, 1H, J = C17H22N4O2: C, 64.95; H, 7.05; N, 17.82; O, 10.18. Found: C,
13.1 Hz), 4.17–4.01 (m, 3H), 1.42 (s, 9H), 1.32 (d, 2H, J = 64.90; H, 7.10; N, 17.78.
6.0 Hz), 1.12–1.03 (m, 1H), 0.85–0.78 (m, 6H) ppm; 13C NMR
General experimental procedure for the synthesis of 14b. To
(75 MHz, CDCl3) δ 154.8, 153.9, 128.8, 80.9, 63.9, 56.0, 46.5, an ice cooled solution of compound 13b (1 equiv.) in dry DCM
32.4, 27.9, 24.6, 15.6, 10.4 ppm; MS (ESI): m/z 281 [M + H]+; (10 mL), Ph3PvCHCO2Et (1.3 equiv.) was added. The reaction
Anal. Calcd for C14H24N4O2: C, 59.98; H, 8.63; N, 19.98; mixture was stirred at room temperature for 2 h. After com-
O, 11.41. Found: C, 59.90; H, 8.67; N, 19.91.
pletion of the reaction, the solvent was evaporated and the
residue was chromatographed over silica gel to furnish 14b as
(S)-tert-Butyl 6-(2-(methylthio)ethyl)-6,7-dihydro-[1,2,3]triazolo-
[1,5-a]pyrazine-5(4H)-carboxylate 11f. Colourless oil; yield, colourless oil.
83%; Rf 0.40 (7/3, hexane–ethyl acetate); [α]3D0 = +16.21 (c 0.15,
(S,E)-Ethyl 4-((tert-butoxycarbonyl) amino)-5-phenylpent-2-
CHCl3); IR (neat, cm−1): 3411, 2918, 2362, 1779, 1431, 1253,
enoate 14b. Colourless oil; yield, 89%; Rf 0.50 (8/2, hexane–
ethyl acetate); [α]D30 = +9.81 (c 0.15, CHCl3); IR (neat, cm−1):
3420, 1735, 1680, 1261, 1154, 791, 673; 1H NMR (300 MHz,
CDCl3) δ 7.23–7.15 (m, 3H), 7.09 (d, 2H, J = 5.2 Hz), 5.78 (d,
1H, J = 12.6 Hz), 4.56 (s, 2H), 4.12–4.07 (m, 2H), 2.85–2.80 (m,
2H), 1.31 (s, 9H), 1.90 (t, 3H, J = 5.3 Hz) ppm; 13C NMR
(75 MHz, CDCl3) δ 166.0, 154.8, 147.5, 136.3, 129.2, 128.4,
126.7, 120.9, 79.6, 60.3, 52.2, 40.7, 28.1, 14.1 ppm; MS (ESI):
m/z 320 [M + H]+; Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89;
N, 4.39; O, 20.04. Found: C, 67.61; H, 7.92; N, 4.32.
General experimental procedure for the synthesis of 15b. To
a stirred solution of compound 14b (1 equiv.) in anhydrous
THF (10 mL), LiAlH4 (3 equiv.) was added portion wise. The
reaction was cooled to 0 °C and stirred for 3 h. The reaction
was quenched by addition of ethyl acetate (30 mL) followed by
water (30 mL) at 0 °C. The aqueous layer was extracted with
ethyl acetate (3 × 50 mL) and the organic layer was dried over
anhydrous Na2SO4. After concentration under vacuum, the
crude product was chromatographed on silica gel(eluent =
hexane–ethyl acetate, 8/2) to furnish the carbinol 15b.
(S)-tert-Butyl 5-hydroxy-1-phenylpentan-2-ylcarbamate 15b.
Colourless oil; yield, 68%; Rf 0.40 (7/3, hexane–ethyl acetate);
[α]3D0 = +17.29 (c 0.13, CHCl3); IR (neat, cm−1): 3329, 1854,
1351, 1291, 981, 793, 674; 1H NMR (300 MHz, CDCl3)
δ 7.24–7.13 (m, 5H), 4.67 (s, 1H), 3.79 (s, 1H), 3.61–3.57 (m, 1H),
3.50–3.45 (m, 1H), 2.76 (d, 2H, J = 5.3 Hz), 1.61 (d, 2H, J = 6.0
Hz), 1.35 (s, 9H), 1.18 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3)
δ 154.4, 143.1, 138.7, 129.7, 126.9, 80.9, 66.2, 58.8, 46.9, 37.7,
29.7, 28.1 ppm; MS (ESI): m/z 280 [M + H]+; Anal. Calcd for
C16H25NO3: C, 68.79; H, 9.02; N, 5.01; O, 17.18. Found: C,
68.71; H, 9.09; N, 4.96.
General experimental procedure for the synthesis of
19b. The procedure was followed as described for 11a–e.
(R)-tert-Butyl 6-benzyl-6,7,8,9-tetrahydro-[1,2,3]triazolo[1,5-a]-
[1,4]diazocine-5(4H)-carboxylate 19b. Colourless oil; yield, 84%;
Rf 0.42 (7/3, hexane–ethyl acetate); [α]3D0 = +28.41 (c 0.11,
CHCl3); IR (neat, cm−1): 3278, 3023, 1681, 1391, 1121, 781,
673; 1H NMR (300 MHz, CDCl3) δ 7.55 (s, 1H), 7.25–7.17 (m,
3H), 7.06–7.01 (m, 2H), 5.13–4.71 (m, 2H), 4.71 (d, 1H, J =
1
1213, 762; H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), 2.44–2.42
(m, 5H), 2.11–2.10 (m, 5H), 2.07 (s, 3H), 1.38 (s, 9H) ppm;
13C NMR (75 MHz, CDCl3) δ 155.4, 147.9, 136.6, 79.7, 56.5,
55.1, 40.8, 33.8, 30.9, 28.7, 15.9 ppm; MS (ESI): m/z 299
[M + H]+; Anal. Calcd for C13H22N4O2S: C, 52.32; H, 7.43; N,
18.78; O, 10.72; S, 10.75. Found: C, 52.30; H, 7.46; N, 18.77.
General experimental procedure for the synthesis of 12a,
c. A solution of Pd(OAc)2 (7 mol%) and PPh3 (23 mol%) in dry
DMF (2 mL) was stirred at room temperature for 20 min
under an argon atmosphere. Aryl iodide (0.9 mmol), K2CO3
(1.8 mmol) and tetrabutylammonium bromide (7 mol%) were
then added successively and the whole reaction mixture was
allowed to stir at room temperature for another 15 min. A solu-
tion of azido-acetylene 10a,c (1 equiv.) in dry DMF (3 mL) was
added dropwise, followed by the addition of CuI (15 mol%).
The resulting mixture was flushed with argon carefully and
stirred for 45 min at room temperature. After disappearance of
the starting materials (monitored by TLC), the reaction
mixture was allowed to heat at 90 °C for 1 h. The reaction
mixture was diluted with water (20 mL). The aqueous layer was
extracted with ethyl acetate (2 × 50 mL) and the organic layer
was dried over anhydrous Na2SO4. After concentration under
vacuum, the crude product was chromatographed on silica gel
(eluent = hexane–ethyl acetate, 9/1) to furnish 12c (81% yield).
(S)-tert-Butyl 6-isopropyl-3-(4-methoxyphenyl)-6,7-dihydro-
[1,2,3]triazolo[1,5-a]pyrazine-5(4H)-carboxylate 12a. Colourless
oil; yield, 79%; Rf 0.50 (8/2, hexane–ethyl acetate); [α]3D0 = +22.0
(c 0.15, CHCl3); IR (neat, cm−1): 3467, 1752, 1362, 1290, 1073,
1
771, 679; H NMR (300 MHz, CDCl3) δ 7.25–7.17 (m, 3H), 7.05
(d, 1H, J = 5.5 Hz), 4.52–4.34 (m, 2H), 4.19–4.15 (m, 2H), 3.76
(s, 3H), 2.68–2.65 (m, 1H), 2.53–2.47 (m, 1H), 1.33 (s, 9H), 1.23
(s, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 163.4, 155.6, 146.9,
143.3, 128.3, 123.0, 114.0, 79.4, 66.6, 56.9, 55.4, 36.4, 28.1,
27.7, 20.6 ppm; MS (ESI): m/z 373 [M + H]+; Anal. Calcd for
C20H28N4O3: C, 64.49; H, 7.58; N, 15.04; O, 12.89. Found: C,
64.47; H, 7.61; N, 15.07.
(S)-tert-Butyl 6-methyl-3-phenyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]-
pyrazine-5(4H) carboxylate 12c. Colourless oil; yield, 81%;
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13.1 Hz), 4.36 (d, 1H, J = 12.9 Hz), 4.25–4.16 (m, 2H), 2.75–2.64
(m, 2H), 2.53–2.47 (m, 2H), 2.02–1.96 (m, 1H), 1.33 (s, 9H)
ppm; 13C NMR (75 MHz, CDCl3) δ 153.8, 136.4, 131.3, 129.1,
128.8, 128.4, 127.0, 81.4, 58.9, 47.0, 40.2, 36.6, 29.6, 28.1,
22.1 ppm; MS (ESI): m/z 343 [M + H]+; Anal. Calcd for
C19H26N4O2: C, 66.64; H, 7.65; N, 16.36; O, 9.34. Found: C,
66.61; H, 7.71; N, 16.30.
8 D. S. Pedersen and A. Abell, The Huisgen Cycloaddition in
Peptidomimetic Chemistry, in Protection Reactions, Medic-
inal Chemistry, Combinatorial Synthesis, ed. A. B. Hughes,
Wiley-VCH, Weinheim, 2011, pp. 101–124.
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Acknowledgements
This research project was supported by CSIR networking project
BSC 0120. Saurav thanks CSIR for providing a fellowship
(NET-SRF). For instrumental facilities from SAIF, CDRI (com-
munication no. 8659/2013/GP), Lucknow is acknowledged.
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